IMiC supplementary material
- 1 Supplementary Material for IMiC Intervention Effects Manuscript
- 2 Baseline characteristics by study and intervention arm
- 3 Intervention effects forest plots and results tables
- 4 Unadjusted estimate forest plots
- 5 Exploratory outcomes (microbiome, proteomics, untargeted metabolomics)
- 6 Subgroup estimates
- 7 Reductions in deficiency of nutrients based on MILQ standards
- 8 Unscaled estimate forest plots
- 9 Trajectory analyses
1 Supplementary Material for IMiC Intervention Effects Manuscript
The online supplement provides the complete analytical outputs from all stages of the study, organized into nine chapters that can be navigated via the Table of Contents on the left. Each chapter corresponds to a major component of the analysis workflow:
- 01_baseline_characteristics presents detailed maternal and infant baseline data across trials and intervention arms
- 02_descriptive_statistics summarizes unadjusted distributions of all milk composition variables
- 04_forest_plots and 05_forest_plots_unadjusted display adjusted and unadjusted intervention effect estimates for each milk constituent across studies
- 06_exploratory_outcomes extends analyses to untargeted metabolomics, proteomics, and microbiome data
- 07_subgroup_estimates provides stratified results (e.g., by maternal BMI, parity, or infant sex)
- 08_sensitivity_results documents robustness checks including per-protocol and model specification tests and
- 09_trajectory_plots visualizes longitudinal changes in milk components over lactation.
test 4
2 Baseline characteristics by study and intervention arm
2.1 Misame
| Control (N=73) |
BEP/BEP (N=66) |
BEP/IFA (N=56) |
IFA/BEP (N=81) |
Overall (N=276) |
|
|---|---|---|---|---|---|
| sex | |||||
| Female | 38 (52.1%) | 29 (43.9%) | 26 (46.4%) | 46 (56.8%) | 139 (50.4%) |
| Male | 35 (47.9%) | 37 (56.1%) | 30 (53.6%) | 35 (43.2%) | 137 (49.6%) |
| mage | |||||
| Mean (SD) | 25.0 (5.28) | 23.4 (5.57) | 24.6 (5.56) | 23.6 (5.83) | 24.1 (5.58) |
| Median [Min, Max] | 24.0 [17.0, 39.0] | 22.5 [16.0, 36.0] | 23.0 [16.0, 40.0] | 23.0 [15.0, 39.0] | 23.0 [15.0, 40.0] |
| meducyrs | |||||
| Mean (SD) | 2.66 (3.38) | 2.36 (3.34) | 3.07 (3.60) | 3.79 (3.95) | 3.00 (3.62) |
| Median [Min, Max] | 2.00 [0, 10.0] | 2.00 [0, 10.0] | 2.00 [0, 10.0] | 2.00 [0, 13.0] | 2.00 [0, 13.0] |
| mhtcm | |||||
| Mean (SD) | 162 (6.68) | 162 (5.05) | 164 (6.02) | 162 (5.35) | 162 (5.82) |
| Median [Min, Max] | 162 [142, 174] | 162 [150, 174] | 163 [151, 178] | 162 [149, 173] | 162 [142, 178] |
| parity | |||||
| Mean (SD) | 2.99 (1.72) | 2.83 (1.71) | 2.95 (1.67) | 2.80 (1.76) | 2.89 (1.71) |
| Median [Min, Max] | 3.00 [1.00, 8.00] | 3.00 [1.00, 7.00] | 3.00 [1.00, 7.00] | 2.00 [1.00, 8.00] | 3.00 [1.00, 8.00] |
| nperson | |||||
| Mean (SD) | 5.92 (4.02) | 6.62 (5.22) | 6.88 (4.05) | 6.21 (5.00) | 6.37 (4.62) |
| Median [Min, Max] | 5.00 [2.00, 23.0] | 5.00 [2.00, 27.0] | 6.00 [2.00, 20.0] | 4.00 [2.00, 30.0] | 5.00 [2.00, 30.0] |
| nrooms | |||||
| Mean (SD) | 2.37 (1.98) | 2.50 (1.68) | 2.46 (1.25) | 2.37 (1.56) | 2.42 (1.65) |
| Median [Min, Max] | 2.00 [1.00, 12.0] | 2.00 [1.00, 9.00] | 2.00 [1.00, 6.00] | 2.00 [1.00, 9.00] | 2.00 [1.00, 12.0] |
| imp_water_src | |||||
| Improved | 41 (56.2%) | 36 (54.5%) | 32 (57.1%) | 53 (65.4%) | 162 (58.7%) |
| Unimproved | 32 (43.8%) | 30 (45.5%) | 24 (42.9%) | 28 (34.6%) | 114 (41.3%) |
| impfloor | |||||
| 0 | 31 (42.5%) | 25 (37.9%) | 23 (41.1%) | 32 (39.5%) | 111 (40.2%) |
| 1 | 42 (57.5%) | 41 (62.1%) | 33 (58.9%) | 49 (60.5%) | 165 (59.8%) |
| missing | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| cookplac | |||||
| 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | |
| missing | 73 (100%) | 66 (100%) | 56 (100%) | 81 (100%) | 276 (100%) |
| No | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Separate space for cooking | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Yes | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| dvseason | |||||
| Early Summer | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Late Summer / Monsoon | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Post-Harvest | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Post monsoon / Autumn | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Pre-Harvest | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Rainy Season | 56 (76.7%) | 56 (84.8%) | 47 (83.9%) | 63 (77.8%) | 222 (80.4%) |
| Summer Season | 17 (23.3%) | 10 (15.2%) | 9 (16.1%) | 18 (22.2%) | 54 (19.6%) |
| Winter | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| dlvloc | |||||
| 0 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| 1 | 3 (4.1%) | 1 (1.5%) | 1 (1.8%) | 2 (2.5%) | 7 (2.5%) |
| 3 | 67 (91.8%) | 61 (92.4%) | 52 (92.9%) | 72 (88.9%) | 252 (91.3%) |
| 4 | 3 (4.1%) | 4 (6.1%) | 3 (5.4%) | 7 (8.6%) | 17 (6.2%) |
| 5 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| hhwealth | |||||
| Mean (SD) | -0.0952 (0.987) | 0.0108 (0.933) | 0.250 (1.03) | -0.161 (1.03) | -0.0190 (1.00) |
| Median [Min, Max] | -0.134 [-2.26, 3.04] | 0.109 [-1.77, 1.86] | 0.216 [-2.04, 2.34] | -0.298 [-2.05, 2.64] | -0.00526 [-2.26, 3.04] |
| hhfoodsecure | |||||
| Mean (SD) | 3.03 (3.20) | 3.17 (2.82) | 3.02 (2.86) | 3.90 (3.93) | 3.32 (3.29) |
| Median [Min, Max] | 2.00 [0, 14.0] | 3.00 [0, 11.0] | 3.00 [0, 12.0] | 4.00 [0, 14.0] | 3.00 [0, 14.0] |
2.2 Mumta
| Control (N=50) |
BEP+ExBf (N=50) |
BEP+ExBf+AZT (N=50) |
Overall (N=150) |
|
|---|---|---|---|---|
| sex | ||||
| Female | 29 (58.0%) | 24 (48.0%) | 31 (62.0%) | 84 (56.0%) |
| Male | 21 (42.0%) | 26 (52.0%) | 19 (38.0%) | 66 (44.0%) |
| mage | ||||
| Mean (SD) | 24.0 (4.77) | 25.2 (5.97) | 23.4 (3.66) | 24.2 (4.92) |
| Median [Min, Max] | 23.0 [17.0, 35.0] | 25.0 [17.0, 37.0] | 24.0 [16.0, 35.0] | 24.0 [16.0, 37.0] |
| meducyrs | ||||
| Mean (SD) | 7.46 (2.05) | 7.96 (1.93) | 8.26 (1.79) | 7.89 (1.94) |
| Median [Min, Max] | 8.00 [2.00, 14.0] | 8.00 [3.00, 12.0] | 8.00 [3.00, 14.0] | 8.00 [2.00, 14.0] |
| mhtcm | ||||
| Mean (SD) | 153 (5.27) | 151 (5.73) | 153 (6.35) | 152 (5.80) |
| Median [Min, Max] | 153 [143, 165] | 151 [142, 165] | 153 [139, 168] | 153 [139, 168] |
| parity | ||||
| Mean (SD) | 2.68 (1.78) | 3.10 (2.38) | 2.42 (1.36) | 2.73 (1.89) |
| Median [Min, Max] | 2.00 [1.00, 8.00] | 3.00 [1.00, 12.0] | 2.00 [1.00, 6.00] | 2.00 [1.00, 12.0] |
| nperson | ||||
| Mean (SD) | 10.2 (3.64) | 9.58 (4.44) | 10.3 (4.57) | 10.0 (4.22) |
| Median [Min, Max] | 10.0 [3.00, 19.0] | 9.00 [3.00, 19.0] | 10.5 [3.00, 18.0] | 10.0 [3.00, 19.0] |
| nrooms | ||||
| Mean (SD) | 2.74 (1.29) | 2.46 (1.51) | 2.58 (1.54) | 2.59 (1.45) |
| Median [Min, Max] | 3.00 [1.00, 6.00] | 2.00 [1.00, 7.00] | 2.00 [1.00, 6.00] | 2.00 [1.00, 7.00] |
| imp_water_src | ||||
| Improved | 48 (96.0%) | 47 (94.0%) | 48 (96.0%) | 143 (95.3%) |
| Unimproved | 2 (4.0%) | 3 (6.0%) | 2 (4.0%) | 7 (4.7%) |
| impfloor | ||||
| 0 | 1 (2.0%) | 1 (2.0%) | 2 (4.0%) | 4 (2.7%) |
| 1 | 49 (98.0%) | 49 (98.0%) | 48 (96.0%) | 146 (97.3%) |
| missing | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| cookplac | ||||
| 1 (2.0%) | 4 (8.0%) | 3 (6.0%) | 8 (5.3%) | |
| missing | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| No | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Separate space for cooking | 49 (98.0%) | 46 (92.0%) | 47 (94.0%) | 142 (94.7%) |
| Yes | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| dvseason | ||||
| Early Summer | 4 (8.0%) | 3 (6.0%) | 7 (14.0%) | 14 (9.3%) |
| Late Summer / Monsoon | 15 (30.0%) | 14 (28.0%) | 16 (32.0%) | 45 (30.0%) |
| Post-Harvest | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Post monsoon / Autumn | 22 (44.0%) | 19 (38.0%) | 13 (26.0%) | 54 (36.0%) |
| Pre-Harvest | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Rainy Season | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Summer Season | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Winter | 9 (18.0%) | 14 (28.0%) | 14 (28.0%) | 37 (24.7%) |
| dlvloc | ||||
| 0 | 13 (26.0%) | 10 (20.0%) | 16 (32.0%) | 39 (26.0%) |
| 1 | 3 (6.0%) | 5 (10.0%) | 5 (10.0%) | 13 (8.7%) |
| 3 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| 4 | 32 (64.0%) | 33 (66.0%) | 27 (54.0%) | 92 (61.3%) |
| 5 | 2 (4.0%) | 2 (4.0%) | 2 (4.0%) | 6 (4.0%) |
| hhwealth | ||||
| Mean (SD) | 0.0389 (0.862) | -0.0987 (1.05) | 0.0598 (1.09) | 0.000000000000000137 (1.00) |
| Median [Min, Max] | 0.0158 [-1.68, 2.09] | -0.246 [-1.68, 2.13] | 0.0942 [-1.68, 1.94] | -0.0227 [-1.68, 2.13] |
| hhfoodsecure | ||||
| Mean (SD) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Median [Min, Max] | 0 [0, 0] | 0 [0, 0] | 0 [0, 0] | 0 [0, 0] |
2.3 Elicit
| Control (N=54) |
Az. (N=45) |
Nico (N=48) |
Nico+Az. (N=53) |
Overall (N=200) |
|
|---|---|---|---|---|---|
| sex | |||||
| Female | 26 (48.1%) | 18 (40.0%) | 28 (58.3%) | 29 (54.7%) | 101 (50.5%) |
| Male | 28 (51.9%) | 27 (60.0%) | 20 (41.7%) | 24 (45.3%) | 99 (49.5%) |
| mage | |||||
| Mean (SD) | 30.8 (7.76) | 28.5 (7.01) | 28.4 (7.00) | 29.5 (6.66) | 29.4 (7.14) |
| Median [Min, Max] | 31.0 [19.0, 42.0] | 26.0 [18.0, 42.0] | 27.0 [19.0, 46.0] | 29.0 [18.0, 46.0] | 28.0 [18.0, 46.0] |
| meducyrs | |||||
| Mean (SD) | 6.85 (2.59) | 6.38 (2.61) | 6.77 (2.43) | 6.19 (2.98) | 6.55 (2.67) |
| Median [Min, Max] | 7.00 [0, 13.0] | 7.00 [0, 12.0] | 7.00 [0, 11.0] | 7.00 [0, 13.0] | 7.00 [0, 13.0] |
| mhtcm | |||||
| Mean (SD) | 158 (5.34) | 157 (4.22) | 158 (5.74) | 158 (6.29) | 158 (5.48) |
| Median [Min, Max] | 159 [144, 168] | 157 [145, 166] | 158 [148, 172] | 158 [143, 178] | 158 [143, 178] |
| parity | |||||
| Mean (SD) | 4.89 (2.83) | 3.98 (2.55) | 3.92 (2.57) | 4.55 (2.58) | 4.36 (2.65) |
| Median [Min, Max] | 5.00 [1.00, 12.0] | 3.00 [1.00, 12.0] | 3.00 [1.00, 9.00] | 5.00 [1.00, 12.0] | 4.00 [1.00, 12.0] |
| nperson | |||||
| Mean (SD) | 7.52 (2.49) | 7.24 (2.89) | 6.81 (2.88) | 7.45 (2.61) | 7.27 (2.70) |
| Median [Min, Max] | 7.00 [3.00, 14.0] | 7.00 [3.00, 14.0] | 7.00 [1.00, 18.0] | 8.00 [3.00, 14.0] | 7.00 [1.00, 18.0] |
| nrooms | |||||
| Mean (SD) | 4.87 (2.18) | 4.58 (2.26) | 4.48 (2.13) | 4.91 (2.26) | 4.72 (2.20) |
| Median [Min, Max] | 4.00 [1.00, 11.0] | 4.00 [1.00, 12.0] | 4.00 [2.00, 11.0] | 5.00 [2.00, 12.0] | 4.00 [1.00, 12.0] |
| imp_water_src | |||||
| Improved | 37 (68.5%) | 30 (66.7%) | 32 (66.7%) | 32 (60.4%) | 131 (65.5%) |
| Unimproved | 17 (31.5%) | 15 (33.3%) | 16 (33.3%) | 21 (39.6%) | 69 (34.5%) |
| impfloor | |||||
| 0 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| 1 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| missing | 54 (100%) | 45 (100%) | 48 (100%) | 53 (100%) | 200 (100%) |
| cookplac | |||||
| 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | |
| missing | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| No | 18 (33.3%) | 16 (35.6%) | 21 (43.8%) | 21 (39.6%) | 76 (38.0%) |
| Separate space for cooking | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Yes | 36 (66.7%) | 29 (64.4%) | 27 (56.3%) | 32 (60.4%) | 124 (62.0%) |
| dvseason | |||||
| Early Summer | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Late Summer / Monsoon | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Post-Harvest | 30 (55.6%) | 30 (66.7%) | 28 (58.3%) | 33 (62.3%) | 121 (60.5%) |
| Post monsoon / Autumn | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Pre-Harvest | 24 (44.4%) | 15 (33.3%) | 20 (41.7%) | 20 (37.7%) | 79 (39.5%) |
| Rainy Season | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Summer Season | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Winter | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| dlvloc | |||||
| 0 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| 1 | 20 (37.0%) | 22 (48.9%) | 22 (45.8%) | 29 (54.7%) | 93 (46.5%) |
| 3 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| 4 | 34 (63.0%) | 23 (51.1%) | 26 (54.2%) | 24 (45.3%) | 107 (53.5%) |
| 5 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| hhwealth | |||||
| Mean (SD) | -0.261 (0.611) | 0.168 (1.13) | -0.0165 (1.08) | 0.139 (1.09) | 0.0000000000000000897 (1.00) |
| Median [Min, Max] | -0.360 [-0.807, 2.32] | -0.137 [-0.807, 5.66] | -0.360 [-0.807, 5.66] | -0.360 [-0.851, 3.43] | -0.360 [-0.851, 5.66] |
| hhfoodsecure | |||||
| Mean (SD) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Median [Min, Max] | 0 [0, 0] | 0 [0, 0] | 0 [0, 0] | 0 [0, 0] | 0 [0, 0] |
3 Intervention effects forest plots and results tables
For each milk modality, the intervention effects are shown in forest plots, faceted by study and visit. Significant effects after FDR correction are shown with solid circles. Intervention average treatment effects are first shown for combined intervention arms (pooling post-natal nutritional intervention arms), and then the effects are shown contrasting each randomized arm against the control arms. Effects are estimated using TMLE, adjusting for baseline prognistic factors. Tables of results are shown below each forest plot, which also include unscaled estimates (in original units of measurement).
3.0.0.1 Macronutrients - combined arms
3.0.0.2 Macronutrients - stratified arms
3.0.0.3 Micronutrients - combined arms
Includes fat-soluble vitamins
3.0.0.4 Micronutrients - stratified arms
3.0.0.5 B-vitamins - combined arms
3.0.0.6 B-vitamins - stratified arms
3.0.0.7 HMOs - combined arms
3.0.0.8 HMOs - stratified arms
3.0.0.9 Bioactives - combined arms
3.0.0.10 Bioactives - stratified arms
4 Unadjusted estimate forest plots
For each milk modality, the intervention effects are shown in forest plots, faceted by study and visit. Significant effects after FDR correction are shown with solid circles. Intervention average treatment effects are first shown for combined intervention arms (pooling post-natal nutritional intervention arms), and then the effects are shown contrasting each randomized arm against the control arms. Effects are estimated using TMLE, unadjusted for baseline prognistic factors.
4.0.0.1 Macronutrients - combined arms
4.0.0.2 Macronutrients - stratified arms
4.0.0.3 Micronutrients - combined arms
4.0.0.4 Micronutrients - stratified arms
4.0.0.5 B-vitamins - combined arms
4.0.0.6 B-vitamins - stratified arms
4.0.0.7 HMOs - combined arms
4.0.0.8 HMOs - stratified arms
4.0.0.9 Bioactives - combined arms
4.0.0.10 Bioactives - stratified arms
5 Exploratory outcomes (microbiome, proteomics, untargeted metabolomics)
5.1 Microbiome
Intervention effects on microbiome diversity measures
Combined arms:
Stratified arms:
Intervention effects on individual microbiome components
Combined arms:
Stratified arms:
5.2 Proteomics
Note- proteomics were taken in a subset of mother-child dyads, and was only taken in the control arm of the Elicit trial, and so intervention effects were not estimatable.
No specific pattern of effects was noted, and the proportion of significant was consisten with false postives under a global null hypothesis.
5.2.1 Combined-arms
5.2.2 Arm-stratified
5.3 Untargeted Metabolomics
6 Subgroup estimates
7 Reductions in deficiency of nutrients based on MILQ standards
-below the 10th percentile -note sparse estimates -TMLE estimates -add citations -add tabulation of cutoffs (including sparse)
(Add figure legend)
8 Unscaled estimate forest plots
8.0.0.1 Macronutrients - combined arms
## Adding missing grouping variables: `measure`8.0.0.2 Macronutrients - stratified arms
## Adding missing grouping variables: `measure`8.0.0.3 Micronutrients - combined arms
## Adding missing grouping variables: `measure`8.0.0.4 Micronutrients - stratified arms
8.0.0.5 B-vitamins - combined arms
## Adding missing grouping variables: `measure`8.0.0.6 B-vitamins - stratified arms
8.0.0.7 HMOs - combined arms
## Adding missing grouping variables: `measure`8.0.0.8 HMOs - stratified arms
8.0.0.9 Bioactives - combined arms
## Adding missing grouping variables: `measure`8.0.0.10 Bioactives - stratified arms
9 Trajectory analyses
9.1 Tables
## Warning in instance$preRenderHook(instance): It seems your data is too big for client-side DataTables. You
## may consider server-side processing: https://rstudio.github.io/DT/server.html## Warning in instance$preRenderHook(instance): It seems your data is too big for client-side DataTables. You
## may consider server-side processing: https://rstudio.github.io/DT/server.html9.2 Trajectory lineplots
## $p_misame_scaled
##
## $p_elicit_scaled
##
## $p_vital_scaled
##
## $p_misame_unscaled
##
## $p_misame_unscaled
##
## $p_vital_unscaled